Loss of GABARAPL1 confers ferroptosis resistance to cancer stem-like cells in hepatocellular carcinoma
- Mol Oncol. 2022 Oct;16(20):3703-3719. doi: 10.1002/1878-0261.13305.
- 1. Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai, China.
- 2. Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, China.
- 3. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
- 4. Department of Gastroenterology, Anhui University of Science and Technology Affiliated Fengxian Hospital, Shanghai Fengxian District Central Hospital, China.
- 5. Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, China.
- 6. Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China.
Cancer stem-like cells (CSLC) are considered a major contributor to the development and progression of hepatocellular carcinoma (HCC). Previous studies indicated that CSLC are characterized by resistance to Ferroptosis, a type of lipid peroxidation-dependent cell death. Here, we identified a set of ferroptosis-related stemness genes (FRSG) and found that these genes may be involved in immune infiltration in HCC. A four-FRSG (CDKN2A, GABARAPL1, HRAS, RPL8) risk model with prognostic prediction was constructed by a COX analysis in HCC. Among these four genes, GABARAPL1 was downregulated in HCC tumor-repopulating cells (TRC; a type of CSLC). Its downregulation decreased the sensitivity of HCC TRC to erastin- or sorafenib-triggered Ferroptosis. Together, we uncovered a molecular mechanism via which CSLC could achieve tolerance to Ferroptosis. Further studies may provide potential therapeutic strategies targeting CSLC in HCC.